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Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia.
Palmer, Duncan S; Howrigan, Daniel P; Chapman, Sinéad B; Adolfsson, Rolf; Bass, Nick; Blackwood, Douglas; Boks, Marco P M; Chen, Chia-Yen; Churchhouse, Claire; Corvin, Aiden P; Craddock, Nicholas; Curtis, David; Di Florio, Arianna; Dickerson, Faith; Freimer, Nelson B; Goes, Fernando S; Jia, Xiaoming; Jones, Ian; Jones, Lisa; Jonsson, Lina; Kahn, Rene S; Landén, Mikael; Locke, Adam E; McIntosh, Andrew M; McQuillin, Andrew; Morris, Derek W; O'Donovan, Michael C; Ophoff, Roel A; Owen, Michael J; Pedersen, Nancy L; Posthuma, Danielle; Reif, Andreas; Risch, Neil; Schaefer, Catherine; Scott, Laura; Singh, Tarjinder; Smoller, Jordan W; Solomonson, Matthew; Clair, David St; Stahl, Eli A; Vreeker, Annabel; Walters, James T R; Wang, Weiqing; Watts, Nicholas A; Yolken, Robert; Zandi, Peter P; Neale, Benjamin M.
Afiliação
  • Palmer DS; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. duncan.stuart.palmer@gmail.com.
  • Howrigan DP; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. duncan.stuart.palmer@gmail.com.
  • Chapman SB; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Adolfsson R; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Bass N; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Blackwood D; Department of Clinical Sciences, Psychiatry, Umea University, Umea, Sweden.
  • Boks MPM; Division of Psychiatry, University College London, London, UK.
  • Chen CY; Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
  • Churchhouse C; Department of Psychiatry, Brain Center UMC Utrecht, Utrecht, the Netherlands.
  • Corvin AP; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Craddock N; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Curtis D; Biogen, Cambridge, MA, USA.
  • Di Florio A; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Dickerson F; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Freimer NB; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Goes FS; Trinity College Dublin, Dublin, Ireland.
  • Jia X; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
  • Jones I; UCL Genetics Institute, University College London, London, UK.
  • Jones L; Centre for Psychiatry, Queen Mary University of London, London, UK.
  • Jonsson L; Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
  • Kahn RS; Sheppard Pratt, Baltimore, MD, USA.
  • Landén M; Department of Psychiatry and Biobehavioral Science, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Locke AE; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • McIntosh AM; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • McQuillin A; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
  • Morris DW; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
  • O'Donovan MC; National Centre for Mental Health, Division of Psychiatry and Clinical Neurosciences, Cardiff University, Cardiff, UK.
  • Ophoff RA; Department of Psychological Medicine, University of Worcester, Worcester, UK.
  • Owen MJ; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • Pedersen NL; Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • Posthuma D; Division of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Reif A; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • Risch N; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • Schaefer C; Division of Genomics & Bioinformatics and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
  • Scott L; Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
  • Singh T; Division of Psychiatry, University College London, London, UK.
  • Smoller JW; Centre for Neuroimaging, Cognition and Genomics, Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.
  • Solomonson M; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
  • Clair DS; Department of Psychiatry and Biobehavioral Science, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Stahl EA; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Vreeker A; Department of Psychiatry, Erasmus Medical Center, Erasmus University, Rotterdam, the Netherlands.
  • Walters JTR; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
  • Wang W; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • Watts NA; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU Amsterdam, Amsterdam, the Netherlands.
  • Yolken R; Department of Psychiatry, Psychosomatic Medicine and Psychiatry, University Hospital Frankfurt - Goethe University, Frankfurt, Germany.
  • Zandi PP; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Neale BM; Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
Nat Genet ; 54(5): 541-547, 2022 05.
Article em En | MEDLINE | ID: mdl-35410376
ABSTRACT
We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10-9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD's polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Esquizofrenia / Transtorno Bipolar Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limite: Humans Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Esquizofrenia / Transtorno Bipolar Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limite: Humans Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos